Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host
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Buti-2011-May-Helicobacter pylori.pdf
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Author(s)
Buti, Ludovico
Spooner, Eric
Van der Veen, Annemarthe G.
Rappuoli, Rino
Covacci, Antonello
Ploegh, Hidde
Date Issued
May 2011
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences
Citation
Buti, L. et al. “Helicobacter Pylori Cytotoxin-associated Gene A (CagA) Subverts the Apoptosis-stimulating Protein of P53 (ASPP2) Tumor Suppressor Pathway of the Host.” Proceedings of the National Academy of Sciences 108.22 (2011) : 9238-9243. ©2011 by the National Academy of Sciences
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Final published version
Abstract
Type I strains of Helicobacter pylori (Hp) possess a pathogenicity island, cag, that encodes the effector protein cytotoxin-associated gene A (CagA) and a type four secretion system. After translocation into the host cell, CagA affects cell shape, increases cell motility, abrogates junctional activity, and promotes an epithelial to mesenchymal transition-like phenotype. Transgenic expression of CagA enhances gastrointestinal and intestinal carcinomas as well as myeloid and B-cell lymphomas in mice, but the mechanism of the induced cancer formation is not fully understood. Here, we show that CagA subverts the tumor suppressor function of apoptosis-stimulating protein of p53 (ASPP2). Delivery of CagA inside the host results in its association with ASPP2. After this interaction, ASPP2 recruits its natural target p53 and inhibits its apoptotic function. CagA leads to enhanced degradation of p53 and thereby, down-regulates its activity in an ASPP2-dependent manner. Finally, Hp-infected cells treated with the p53-activating drug Doxorubicin are more resistant to apoptosis than uninfected cells, an effect that requires ASPP2. The interaction between CagA and ASPP2 and the consequent degradation of p53 are examples of a bacterial protein that subverts the p53 tumor suppressor pathway in a manner similar to DNA tumor viruses. This finding may contribute to the understanding of the increased risk of gastric cancer in patients infected with Hp CagA+ strains.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1073/pnas.1106200108
